A copper(II) complex with β-diketone and 1,10-phenanthroline (CBP-01) triggers cancer cell death: citotoxycity, genotoxicity, acute toxicity and antitumor activity

The use of metal compounds as therapeutic drugs has gained prominence since the discovery of cisplatin. In the attempt to find save and more effective drugs, several metal based-drugs have been synthesized as potential antitumor agents. The use of the essential metals is justified because they are present in living organisms, participating in various biological processes. Among the trace elements it´s found the copper, which is considered an active redox metal that makes it possible the production of reactive oxygen species (ROS), which is considered its main function. In addition, copper is found at higher concentrations in tumor cells when compared to normal cells, which makes it an advantageous essential metal for new drugs development. Several studies have demonstrated that the complexation of copper with other ligands has provided the ability to cleave the DNA molecule, thus instigating the synthesis and characterization of new copper(II)-based complexes such as [Cu(BTA)phen]ClO4, evaluated in the present work. The [Cu(BTA)phen]ClO4 complex showed in vitro and in vivo antitumor activity. The mechanism of action of the complex is related to the redox reaction of the compound, which causes the production of ROS, aiding the direct or indirect action of the complex on the DNA, promoting the entrapment of the tumor cells in the G0/G1 phase and, consequently, inducting cell death. Evidences have shown that cell death is initiated by autophagy dysfunction, culminating in the induction of apoptosis. It was also observed that the complex under display selectivity to the tumor cells tested in vitro. Besides, in vivo assays showed that the complex possess potential antitumor, once that it reduce solid tumor volume in proportions very similar to cisplatin. It is noteworthy that the [Cu(BTA)phen]ClO4 complex presented lower toxicity during treatment when compared to cisplatin, which is evidenced by the weight loss observed in the cisplatin treated group. Therefore, the complex under study may be considered a promising antitumor agent.CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorCNPq - Conselho Nacional de Desenvolvimento Científico e TecnológicoFAPEMIG - Fundação de Amparo a Pesquisa do Estado de Minas GeraisDissertação (Mestrado)O uso de compostos metálicos como fármacos vem ganhando destaque desde a descoberta da cisplatina e na tentativa de encontrar complexos mais seguros e efetivos, vários compostos tendo como base metais essenciais têm sido sintetizados. O uso dos metais essenciais é justificado por eles estarem presentes nos organismos vivos participando de diversos processos biológicos. Dentre os elementos traços destaca-se o cobre, que é considerado um metal redox ativo, o que possibilita a produção de espécies reativas de oxigênio (ROS), sendo esta considerada sua principal função. Além disso, o cobre é encontrado em maiores concentrações nas células tumorais, quando comparado com as células normais, tornando-o assim um metal essencial vantajoso para ser estudado. Diversos estudos demonstraram que complexos de cobre possuem a capacidade de clivar a molécula de DNA, instigando assim a síntese e caracterização de novos complexos a base de cobre(II) como o [Cu(BTA)phen]ClO4, estudado no presente trabalho. O complexo [Cu(BTA)phen]ClO4 apresentou atividade antitumoral in vitro e in vivo. Além disso, o complexo apresentou seletividade perante as células tumorais testadas in vitro. O mecanismo de ação pode estar relacionado com a reação redox do composto, que ocasiona a produção de ROS, auxiliando a ação direta ou indireta do complexo sobre o DNA, promovendo assim, o aprisionamento das células tumorais na fase G0/G1 e, consequentemente, a indução da morte celular. Evidencias mostraram que a morte celular é iniciada pela disfunção da autofagia, culminando na indução da apoptose. Os ensaios in vivo mostraram que o complexo apresentou potencial atividade de agente antitumoral, a partir da redução do volume do tumor sólido em proporções similares à cisplatina. Vale ressaltar que o complexo [Cu(BTA)phen]ClO4 apresentou menor toxicidade durante o tratamento quando comparado com a cisplatina, sendo esse fato evidenciado pela perda de peso observada no grupo tratado com a cisplatina. Portanto, o complexo em estudo pode ser considerado um promissor agente antitumoral

A New Approach to Inhibiting Triple-Negative Breast Cancer: In Vitro, Ex Vivo and In Vivo Antiangiogenic Effect of BthTx-II, a PLA₂-Asp-49 from <i>Bothrops jararacussu</i> Venom

Phospholipases A2 (PLA2) represent a superfamily of enzymes widely distributed in living organisms, with a broad spectrum of pharmacological activities and therapeutic potential. Anti-angiogenic strategies have become one of the main tools in fighting cancer. In this sense, the present work reports the inhibition of tumor angiogenesis induced by Asp-49 BthTX-II using in vitro, ex vivo and in vivo approaches. We demonstrate that BthTx-II inhibited cell adhesion, proliferation, and migration of human umbilical vein endothelial cells (HUVEC), as well as caused a reduction in the levels of endothelial growth factor (VEGF) during in vitro angiogenesis assays. BthTx-II was also able to inhibit the sprouting angiogenic process, by the ex vivo germination assay of the aortic ring; in addition, this toxin inhibited the migration and proliferation of HUVEC in co-culture with triple-negative breast cancer cells (e.g., MDA-MB-231 cells). Finally, in vivo tumor suppression and anti-angiogenic activities were analyzed using MDA-MB-231 cells with Matrigel injected into the chorioallantoic membrane of chicken embryo (CAM) for 7 days treatment with BthTx-II, showing a considerable reduction in vessel caliber, on the size and weight of tumors. Together, these results suggest an important antiangiogenic and antitumor role for BthTx-II, as a potential prototype for the development of new tools and antitumor drugs in cancer therapy

Oxidative stress induced by Pollonein-LAAO, a new L-amino acid oxidase from Bothrops moojeni venom, prompts prostate tumor spheroid cell death and impairs the cellular invasion process in vitro.

peer reviewedCancer cells produce abnormal levels of reactive oxygen species (ROS) that contribute to promote their malignant phenotype. In this framework, we hypothesized that the change in ROS concentration above threshold could impair key events of prostate cancer cells (PC-3) progression. Our results demonstrated that Pollonein-LAAO, a new L-amino acid oxidase obtained from Bothrops moojeni venom, was cytotoxic to PC-3 cells in two-dimensional and in tumor spheroid assays. Pollonein-LAAO was able to increase the intracellular ROS generation that culminates in cell death from apoptosis by both intrinsic and extrinsic pathways due to the up-regulation of TP53, BAX, BAD, TNFRSF10B and CASP8. Additionally, Pollonein-LAAO reduced mitochondrial membrane potential and caused G0/G1 phase to delay, due to the up-regulation of CDKN1A and the down-regulation of the expression of CDK2 and E2F. Interestingly, Pollonein-LAAO inhibited critical steps of the cellular invasion process (migration, invasion and adhesion), due to the down-regulation of SNAI1, VIM, MMP2, ITGA2, ITGAV and ITGB3. Furthermore, the Pollonein-LAAO effects were associated with the intracellular ROS production, since the presence of catalase restored the invasiveness of PC-3 cells. In this sense, this study contributes to the potential use of Pollonein-LAAO as ROS-based agent to enhance the current understanding of cancer treatment strategies

Crystal structure, anti-trypanosoma cruzi and cytotoxic activities of Cu(II) complexes bearing beta-diketone and alpha-diimine ligands

Three novel copper(II) complexes were synthesized: [Cu(tfa)(2)] (I), [Cu(tfa)(dmb)(NO3)]center dot 1.5H(2)O (II) and [Cu(tfa)(nphen)(NO3)] (III), where tfa = 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione, nphen = 5-nitro-1,10-phenanthroline and dmb = 4,4-dimethoxy-2,2-bipyridine. They were characterized by elemental analysis, conductivity measurements, FT-IR, UV-Vis and single-crystal X-ray diffraction. The X-ray crystal structures of I, II and III reveal that the beta-diketone coordinates via the oxygen atoms, while the heterocyclic bases coordinate via their two nitrogen atoms. The cytotoxic activity of I, II and III was investigated in two tumor cell lines (Ehrlich tumor and sarcoma 180) and in a non-tumor cell line (myoblast C2C12). Complex DI exhibited good activity (IC50 (Ehrlich) = 15.75 mu M and IC50 (sarcoma )180 = 16.90 mu M) and selectivity (SI > 4) in both tumor cell lines. Subsequently, it was found that III also present good activity against Trypanosoma cruzi499CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE MINAS GERAIS - FAPEMIGFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP305190/2017-2não temnão tem2016/08823-4; 2013/07581-

Shedding Lights on Crude Venom from Solitary Foraging Predatory Ant <i>Ectatomma opaciventre</i>: Initial Toxinological Investigation

Some species of primitive predatory ants, despite living in a colony, exercise their hunting collection strategy individually; their venom is painful, paralyzing, digestive, and lethal for their prey, yet the toxins responsible for these effects are poorly known. Ectatomma opaciventre is a previously unrecorded solitary hunting ant from the Brazilian Cerrado. To overcome this hindrance, the present study performed the in vitro enzymatic, biochemical, and biological activities of E. opaciventre to better understand the properties of this venom. Its venom showed several proteins with masses ranging from 1–116 kDa, highlighting the complexity of this venom. Compounds with high enzymatic activity were described, elucidating different enzyme classes present in the venom, with the presence of the first L-amino acid oxidase in Hymenoptera venoms being reported. Its crude venom contributes to a state of blood incoagulability, acting on primary hemostasis, inhibiting collagen-induced platelet aggregation, and operating on the fibrinolysis of loose red clots. Furthermore, the E. opaciventre venom preferentially induced cytotoxic effects on lung cancer cell lines and three different species of Leishmania. These data shed a comprehensive portrait of enzymatic components, biochemical and biological effects in vitro, opening perspectives for bio-pharmacological application of E. opaciventre venom molecules

Biochemical characterization and assessment of leishmanicidal effects of a new L-amino acid oxidase from Crotalus durissus collilineatus snake venom (CollinLA AO-I).

peer reviewedThis study reports the isolation of CollinLAAO-I, a new L-amino acid oxidase from Crotalus durissus collilineatus snake venom, its biochemical characterization and leishmanicidal potential in Leishmania spp. CollinLAAO-I (63.1 kDa) was successfully isolated with high purity using two chromatographic steps and represents 2.5% of total venom proteins. CollinLAAO-I displayed high enzymatic activity (4262.83 U/mg/min), significantly reducing after 28 days. The enzymatic activity of CollinLAAO-I revealed higher affinity for hydrophobic amino acids such as L-leucine, high enzymatic activity in a wide pH range (6.0-10.0), at temperatures from 0 to 25 °C, and showed complete inhibition in the presence of Na+ and K+. Cytotoxicity assays revealed IC50 of 18.49 and 11.66 μg/mL for Leishmania (L.) amazonensis and Leishmania (L.) infantum, respectively, and the cytotoxicity was completely suppressed by catalase. CollinLAAO-I significantly increased the intracellular concentration of reactive oxygen species (ROS) and reduced the mitochondrial potential of both Leishmania species. Furthermore, CollinLAAO-I decreased the parasite capacity to infect macrophages by around 70%, indicating that even subtoxic concentrations of CollinLAAO-I can interfere with Leishmania vital processes. Thus, the results obtained for CollinLAAO-I provide important support for developing therapeutic strategies against leishmaniasis

Conceptos clave de la gestión cultural. Volumen I

Esta obra tiene como objetivo brindar un primer acercamiento al lenguaje de la gestión cultural en Latinoamérica. Un intento de poner en palabras, de realizar una reflexión de lo que se hace y se piensa desde diversos luga res de nuestras múltiples y extensas realidades que nos caracterizan. Como tal, estos conceptos que presentamos están abiertos y en movimiento, y a partir de ello se pueden armar y desarmar, construir y deconstruir, diversos enfoques y tendencias que buscan dar sentido a una gestión cultural latinoamericana que se encuentra en la búsqueda de sí misma. En gran parte de la historia de nuestra práctica, hemos recibido las influencias externas de las formas de hacer, pensar y nombrar la acción cultural. Por tal motivo, y como resultado de múltiples procesos de formalización o profesionalización, nos vemos en la necesidad de tener claridad de los conceptos y diseñar formas posibles de deslindar campos respecto a las importaciones, en muchos casos mecánicas y fuera de lugar, al mismo tiempo que nos llevan a revisar críticamente la forma en que nos vemos y somos vistos. Los términos aquí expuestos buscan dar sentido a una práctica que se viene realizando desde hace muchos años y que necesita ser pensada. No pretenden ser homogéneos ni hegemónicos, sino contribuir a la reflexión de una gestión cultural que cada vez más se perfila como la posibilidad de constituirse en un referente de la acción cultural en Latinoamérica